Gilbert's syndrome

Gilbert's syndrome (GS) is a syndrome in which the liver of affected individuals processes bilirubin more slowly than the majority, resulting in higher levels in the blood.<ref name="GARD2016">Template:Cite web</ref> Many people never have symptoms.<ref name="GARD2016" /> Occasionally jaundice (a yellowing of the skin or whites of the eyes) may occur.<ref name="GARD2016" />

Gilbert syndrome is due to a genetic variant in the UGT1A1 gene, which results in decreased activity of the bilirubin uridine diphosphate glucuronosyltransferase enzyme.<ref name="GARD2016" /><ref name="GHR2017" /> It is typically inherited in an autosomal recessive pattern and occasionally in an autosomal dominant pattern depending on the type of variant.<ref name="GHR2017" /> Episodes of jaundice may be triggered by stress such as exercise, menstruation, or not eating.<ref name="GHR2017">Template:Cite web</ref> Diagnosis is based on elevated levels of unconjugated bilirubin in the blood without signs of liver problems or red blood cell breakdown.<ref name="Rare2015">Template:Cite web</ref><ref name="GHR2017" />

Typically, no treatment is needed.<ref name=GARD2016/> Phenobarbital aids in the conjugation of bilirubin and can be prescribed if jaundice becomes significant.<ref name=GARD2016/> Gilbert syndrome is associated with decreased cardiovascular health risks but increased risks of some cancers and gallstones.<ref name="Bulmer-2013" /><ref name="Beutler-2024" /> Gilbert syndrome affects about 5% of people in the United States.<ref name=GHR2017/> Males are more often diagnosed than females.<ref name=GARD2016/> It is often not noticed until late childhood to early adulthood.<ref name=Rare2015/> The condition was first described in 1901 by Augustin Nicolas Gilbert.<ref name="Gilbert & Lereboullet, Semaine Médicale, 1901" /><ref name=Rare2015/><ref name=WHO2017>Template:Cite web</ref>

Signs and symptoms

Jaundice

Gilbert syndrome produces an elevated level of unconjugated bilirubin in the bloodstream, but normally has no consequences. Mild jaundice may appear under conditions of exertion, stress, fasting, and infections, but the condition is otherwise usually asymptomatic.<ref>Kasper et al., Harrison's Principles of Internal Medicine, 16th edition, McGraw-Hill 2005</ref><ref>Boon et al., Davidson's Principles & Practice of Medicine, 20th edition, Churchill Livingstone 2006</ref> Severe cases are seen by yellowing of the skin tone and yellowing of the conjunctiva in the eye.<ref>Template:Cite web</ref>

Gilbert syndrome has been reported to contribute to an accelerated onset of neonatal jaundice. The syndrome cannot cause severe indirect hyperbilirubinemia in neonates by itself, but it may have a summative effect on rising bilirubin when combined with other factors,<ref name="pmid21403409">Template:Cite journal</ref> for example in the presence of increased red blood cell destruction due to diseases such as G6PD deficiency.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> This situation can be especially dangerous if not quickly treated, as the high serum bilirubin can cause irreversible neurological disability in the form of kernicterus.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite book</ref>

Effects on drug metabolism and drug interactions

The enzymes that are defective in GS – UDP glucuronosyltransferase 1 family, polypeptide A1 (UGT1A1) – are also responsible for some of the liver's ability to detoxify certain drugs. For example, Gilbert syndrome is associated with severe diarrhea and neutropenia in patients who are treated with irinotecan, which is metabolized by UGT1A1.<ref>Template:Cite journal</ref>

While paracetamol (acetaminophen) is not metabolized by UGT1A1,<ref>Template:Cite journal</ref> it is metabolized by one of the other enzymes also deficient in some people with GS.<ref>Template:Cite journal</ref><ref name=esteban>Template:Cite journal</ref> A subset of people with GS may have an increased risk of paracetamol toxicity.<ref name=esteban/><ref name="Mukherjee"/>

Another drug that has increased adverse side-effects in individuals with Gilbert syndrome is atazanavir.<ref name="Strassburg-2008">Strassburg, C. P. (2008). Pharmacogenetics of gilbert's syndrome. Pharmacogenomics, 9(6), 703-15. doi:https://doi.org/10.2217/14622416.9.6.703</ref> Atazanavir is a protease inhibitor for the treatment of HIV.<ref name="Strassburg-2008" /> Atazanavir can lead to jaundice in individuals with Gilbert syndrome because it further inhibits the UGT enzymes that already exhibit decreased activity in Gilbert syndrome.<ref name="Strassburg-2008" />

Cardiovascular effects

The mild increase in unconjugated bilirubin due to Gilbert syndrome is closely related to the reduction in the prevalence of chronic diseases, especially cardiovascular disease and type 2 diabetes, related risk factors, and all-cause mortality.<ref>Template:Cite journal</ref> Observational studies emphasize that the antioxidant effects of unconjugated bilirubin may bring survival benefits to patients.<ref>Template:Cite journal</ref>

Several analyses have found a significantly decreased risk of coronary artery disease (CAD) in individuals with GS.<ref name="2002meta">Template:Cite journal</ref><ref name="2008meta">Template:Cite journal</ref>

Specifically, people with mildly elevated levels of bilirubin (1.1 mg/dl to 2.7 mg/dl) were at lower risk for CAD and at lower risk for future heart disease.<ref name="Vitek GS ischemic">Template:Cite journal</ref> These researchers went on to perform a meta-analysis of data available up to 2002, and confirmed the incidence of atherosclerotic disease (hardening of the arteries) in subjects with GS had a close and inverse relationship to the serum bilirubin.<ref name="2002meta" /> This beneficial effect was attributed to bilirubin IXα which is recognized as a potent antioxidant, rather than confounding factors such as high-density lipoprotein levels.<ref name="Vitek GS ischemic"/>

This association was also seen in long-term data from the Framingham Heart Study.<ref>Template:Cite journal</ref><ref name="Bulmer-2013">Template:Cite journal</ref>Template:Primary source inline Moderately elevated levels of bilirubin in people with GS and the (TA)₇/(TA)₇ genotype were associated with one-third the risk for both coronary heart disease and cardiovascular disease as compared to those with the (TA)₆/(TA)₆ genotype (i.e. a normal, nonmutated gene locus).

Platelet counts and MPV (mean platelet volume) are decreased in patients with Gilbert's syndrome. The elevated levels of bilirubin and decreasing levels of MPV and CRP in Gilbert's syndrome patients may have an effect on the slowing down of the atherosclerotic process.<ref>Template:Cite journal</ref>

Other symptoms and links to disease

Symptoms, whether connected or not to GS, have been reported in a subset of those affected: fatigue (feeling tired all the time), difficulty maintaining concentration, unusual patterns of anxiety, loss of appetite, nausea, abdominal pain, loss of weight, itching (with no rash), and others,<ref name=GSC>GilbertsSyndrome.com Template:Webarchive</ref> such as humor change or depression. But scientific studies found no clear pattern of adverse symptoms related to the elevated levels of unconjugated bilirubin in adults. However, other substances glucuronidized by the affected enzymes in those with Gilbert's syndrome could theoretically, at their toxic levels, cause these symptoms.<ref name=dispute>Template:Cite journal</ref><ref name="Bailey does it exist">Template:Cite journal</ref> Consequently, debate exists about whether GS should be classified as a disease.<ref name=dispute/><ref>Template:Cite journal</ref>

Gilbert syndrome has been linked to an increased risk of gallstones, schizophrenia, breast cancer, and colorectal cancer.<ref name="GSC" /><ref>Template:Cite journal</ref><ref name="Beutler-2024" /> The theorized mechanism for the increased risk of breast cancer is elevated estrogen from its decreased metabolism by UDP-glucuronosyltransferase in those with Gilbert syndrome. <ref name="Beutler-2024" /> The cause for the increased risk of schizophrenia is not yet fully understood and is the object of further research.<ref name="Beutler-2024" />

Cause

Mutations in the UGT1A1 gene lead to Gilbert Syndrome.<ref>Template:Cite web</ref> The gene provides instructions for making the bilirubin uridine diphosphate glucuronosyltransferase (bilirubin-UGT) enzyme, which can be found in the liver cells and is responsible for preparing bilirubin for removal from the body.<ref name="medlineplus1">Template:Cite web</ref>

The bilirubin-UGT enzyme performs a chemical reaction called glucuronidation. Glucuronic acid is transferred to unconjugated bilirubin, which is a yellowish pigment made when your body breaks down old red blood cells,<ref>Template:Cite web</ref> and then being converted to conjugated bilirubin during the reaction. Conjugated bilirubin passes from the liver into the intestines with bile. It's then excreted in stool.

People with Gilbert syndrome have approximately 30 percent of normal bilirubin-UGT enzyme function, which contributes to a lower rate of glucuronidation of unconjugated bilirubin. This substance then accumulates in the body, causing mild hyperbilirubinemia.<ref name="medlineplus1"/>

Genetics

Gilbert syndrome is a phenotypic effect, mostly associated with increased blood bilirubin levels, but also sometimes characterized by mild jaundice due to increased unconjugated bilirubin, that arises from several different genotypic variants of the gene for the enzyme responsible for changing bilirubin to the conjugated form.<ref name="Beutler-2024">Beutler K, Lewandowski J. Gilbert's syndrome - bright and dark sides of the disease - literature review. Journal of Education, Health and Sport. 2024;63:146-154. doi:10.12775/JEHS.2024.63.011</ref>

Gilbert's syndrome is characterized by a 70–80% reduction in the glucuronidation activity of the enzyme (UGT1A1). The UGT1A1 gene is located on human chromosome 2.<ref name=nlm54658>Template:Cite web</ref>

More than 100 polymorphisms of the UGT1A1 gene are known, designated as UGT1A1*n (where n is the general chronological order of discovery), either of the gene itself or of its promoter region. UGT1A1 is associated with a TATA box promoter region; this region most commonly contains the genetic sequence A(TA)₆TAA; this variant accounts for about 50% of alleles in many populations. However, several allelic polymorphic variants of this region occur, the most common of which results from adding another dinucleotide repeat TA to the promoter region, resulting in A(TA)₇TAA, which is called UGT1A1*28; this common variant accounts for about 40% of alleles in some populations, but is seen less often, around 3% of alleles, in Southeast and East Asian people and Pacific Islanders.Template:Cn

In most populations, Gilbert syndrome is most commonly associated with homozygous A(TA)₇TAA alleles.<ref>Template:Cite journal</ref><ref name="Bosma UDP-1">Template:Cite journal</ref><ref>Template:Cite journal</ref> In 94% of GS cases, two other glucuronosyltransferase enzymes, UGT1A6 (rendered 50% inactive) and UGT1A7 (rendered 83% ineffective), are also affected.Template:Cn

However, Gilbert syndrome can arise without TATA box promoter polymorphic variants; in some populations, particularly healthy Southeast and East Asians, Gilbert's syndrome is more often a consequence of heterozygote missense mutations (such as Gly71Arg also known as UGT1A1*6, Tyr486Asp also known as UGT1A1*7, Pro364Leu also known as UGT1A1*73) in the actual gene coding region,<ref name="Mukherjee">Template:EMedicine</ref> which may be associated with significantly higher bilirubin levels.<ref name="Mukherjee" />

Because of its effects on drug and bilirubin breakdown and because of its genetic inheritance, Gilbert's syndrome can be classed as a minor inborn error of metabolism.Template:Cn

Diagnosis

Gilbert syndrome is typically diagnosed based on clinical findings and laboratory results, emphasizing the exclusion of other potential causes of elevated bilirubin levels. The key criteria include:

1. Mild, Unconjugated Hyperbilirubinemia:
   • Total serum bilirubin levels are mildly elevated, typically remaining below 6 mg/dL (102 μmol/L), with a predominance of the unconjugated (indirect) fraction.<ref>Template:Cite web</ref>
2. Normal Liver Function Tests:
   • Liver enzymes, including alanine aminotransferase (ALT) and aspartate aminotransferase (AST), are within normal ranges, indicating no underlying liver disease.<ref name="Vítek-2023">Template:Cite journal</ref>
3. Absence of Hemolysis:
   • No evidence of increased red blood cell breakdown, as indicated by normal hemoglobin levels and reticulocyte counts.<ref name="Vítek-2023" />
4. Intermittent Nature of Symptoms:
   • Episodes of jaundice that may be triggered by factors such as fasting, illness, stress, or exertion, with no other associated symptoms.<ref>Template:Cite web</ref> The level of total bilirubin is often further increased if the blood sample is taken after fasting for two days,<ref>Template:Cite journal</ref> and a fast can, therefore, be useful diagnostically. A further conceptual step that is rarely necessary or appropriate is to give a low dose of phenobarbital:<ref>Template:Cite journal</ref> the bilirubin will decrease substantially.
5. Exclusion of Other Liver Disorders:
   • No clinical or laboratory evidence of other liver diseases; imaging studies and serologic tests for hepatitis are negative.<ref name="Vítek-2023" />
6. Genetic Testing:
   • Identification of mutations in the UGT1A1 gene can confirm the diagnosis of Gilbert syndrome. While not routinely required, genetic testing may be considered in cases where the diagnosis is uncertain or to provide reassurance to patients.<ref>Template:Citation</ref>

Differential diagnosis

While Gilbert syndrome is considered harmless, it is clinically important because it may give rise to a concern about a blood or liver condition, which could be more dangerous. However, these conditions have additional indicators:

• In Gilbert syndrome, unless another disease of the liver is also present, the liver enzymes ALT/SGPT and AST/SGOT, as well as albumin, are within normal ranges.<ref name="Vítek-2023" />
• Crigler–Najjar syndrome (types I and II), a different glucuronyl transferase disorder, is much more severe, with 0–10% UGT1A1 activity,<ref name="Singh-2023">Template:Cite book</ref> with affected individuals at risk of brain damage in infancy (type I) and teenage years (type II).<ref name="Singh-2023" />
• Hemolysis of any cause can be excluded by a full blood count, haptoglobin, lactate dehydrogenase levels, and the absence of reticulocytosis (elevated reticulocytes in the blood would usually be observed in haemolytic anaemia).<ref>Template:Cite web</ref>
• Dubin–Johnson syndrome and Rotor syndrome are rarer autosomal recessive disorders characterized by an increase of conjugated bilirubin.
• Viral hepatitis associated with increase of conjugated bilirubin can be excluded by negative blood samples for antigens specific to the different hepatitis viruses.
• Cholestasis can be excluded by normal levels of bile acids in plasma, the absence of lactate dehydrogenase, low levels of conjugated bilirubin, and ultrasound scan of the bile ducts.<ref>Template:Citation</ref>
• Vitamin B12 deficiency - elevated bilirubin levels (and MCV counts above 90–92) can be associated with a vitamin B12 deficiency.<ref>Template:Cite journal</ref>

Treatment

Gilbert's syndrome is a benign condition that typically requires no medical treatment.<ref name="Cleveland Clinic">Template:Cite web</ref> The primary approach involves patient education and reassurance about the harmless nature of the syndrome.<ref name="Cleveland Clinic" /> Episodes of jaundice, when they occur, are usually mild and resolve on their own without intervention.<ref name="Cleveland Clinic" /> To minimize the frequency of these episodes, individuals are advised to avoid known triggers such as fasting, dehydration, stress, and strenuous physical exertion.<ref name="Cleveland Clinic" /> Maintaining a healthy lifestyle, including regular meals and adequate hydration, can help manage the condition effectively.<ref name="Cleveland Clinic" /> If jaundice is significant, phenobarbital may be used.<ref name=GARD2016/>

Research directions

Vitamin levels

Studies conducted so far suggest that subjects with GS may have lower levels of vitamin D and folic acid than control subjects, having these levels inversely correlated with bilirubin levels. It may be that GS may impair the metabolism or absorption of these vitamins, or that these vitamins may affect the expression or activity of the UGT1A1 enzyme that is responsible for bilirubin conjugation. However, these studies had limitations, such as the small sample size, the lack of a standardized definition of GS, the possible confounding factors of diet, lifestyle, and medication use, and the cross-sectional and observational design that does not allow for causal inference.<ref name="pmid30717703">Template:Cite journal</ref>

The role of bilirubin in health and disease

Ongoing studies suggest that mild hyperbilirubinemia in GS may have beneficial effects, probably due to bilirubin's antioxidant and anti-inflammatory properties. Hyperbilirubinemia in GS may protect against oxidative stress and inflammation-related diseases, such as cardiovascular diseases, cancers, diabetes, and neurodegenerative disorders. However, the mechanisms and pathways of bilirubin protection are not fully elucidated, and the optimal level and range of bilirubin are unknown. The genetic and environmental factors that influence UGT1A1 expression and activity are also poorly characterized and may affect the variability and penetrance of GS.<ref name="pmid37390966"/> Despite the fact that hyperbilirubinemia in GS is associated with reduced incidence of cardiovascular diseases,<ref name="pmid31889709">Template:Cite journal</ref> diabetes, and metabolic syndrome,<ref name="pmid34679671">Template:Cite journal</ref> the clinical significance and implications of these GS research findings are unclear, and can not yet be translated into preventive or therapeutic strategies.<ref name="pmid37390966">Template:Cite journal</ref>

History

Gilbert syndrome was first described by French gastroenterologist Augustin Nicolas Gilbert and co-workers in 1901.<ref name=WHO2017/><ref name="Gilbert & Lereboullet, Semaine Médicale, 1901">Template:Cite journal</ref> In German literature, it is commonly associated with Jens Einar Meulengracht.<ref>Template:WhoNamedIt</ref>

Alternative, less common names for this disorder include:

• Familial benign unconjugated hyperbilirubinaemia
• Constitutional liver dysfunction
• Familial non-hemolytic non-obstructive jaundice
• Icterus intermittens juvenilis
• Low-grade chronic hyperbilirubinemia
• Unconjugated benign bilirubinemia

Society and culture

Notable cases

• Napoleon<ref name="Foulk">Template:Cite journal</ref>
• Arthur Kornberg, Nobel laureate in Physiology or Medicine, 1959<ref name="Shmaefsky">Template:Cite book</ref>
• Nicky Wire, Manic Street Preachers bassist<ref name="swep">Template:Cite news</ref>
• Alexandr Dolgopolov (tennis player)<ref>Template:Cite news</ref>
• Jonas Folger, MotoGP rider.<ref>Template:Cite web</ref>

External links

• Understanding Gilbert's Syndrome and living better with Gilbert's Syndrome symptoms
• Template:RareDiseases
• Gilbert's Syndrome Template:Webarchive BMJ Best Practices monograph